Adrenal hormones mediate disease tolerance in malaria

Abstract

Malaria reduces host fitness and survival by pathogen-mediated damage and inflammation. Disease tolerance mechanisms counter these negative effects without decreasing pathogen load. Here, we demonstrate that in four different mouse models of malaria, adrenal hormones confer disease tolerance and protect against early death, independently of parasitemia. Surprisingly, adrenalectomy differentially affects malaria-induced inflammation by increasing circulating cytokines and inflammation in the brain but not in the liver or lung. Furthermore, without affecting the transcription of hepatic gluconeogenic enzymes, adrenalectomy causes exhaustion of hepatic glycogen and insulin-independent lethal hypoglycemia upon infection. This hypoglycemia is not prevented by glucose administration or TNF-α neutralization. In contrast, treatment with a synthetic glucocorticoid (dexamethasone) prevents the hypoglycemia, lowers cerebral cytokine expression and increases survival rates. Overall, we conclude that in malaria, adrenal hormones do not protect against lung and liver inflammation. Instead, they prevent excessive systemic and brain inflammation and severe hypoglycemia, thereby contributing to tolerance.

The olfactory mucosa, first actor of olfactory detection, is sensitive to glucocorticoid hormone

“…Our results differ slightly between treatment of OM primary cultures and in vivo injections; this is probably because no OSN was detected in our cultures in the absence of specific growth factors in the media (Gouadon et al., ), whereas the whole in vivo OM contains much more diverse cellular types. The injected dexamethasone dose used is consistent with what has been successfully used for in vivo rodent GR activation (Caldefie‐Chezet et al., ; Thiebaud et al., ; Vandermosten et al., ), those studies report using 1.5–24 mg/kg, which supports the suitability of our model.…”

“…In order to investigate the physiological role of GR in the OM, we carried out experiments in a rat model of acute HPA axis activation, using a single supraphysiological dose of DEX. This dose was selected based on literature searches, in order to activate GR strongly, while avoiding the DEX‐induced repression of the HPA axis, through GR‐mediated negative feedback (see discussion below and Vandermosten et al., ).…”

Malarial Inflammation-Driven Pathophysiology and Its Attenuation by Triterpene Phytotherapeutics

“…Complications of malaria including CM, SMA, placental malaria, hypoglycemia, ARDS are not efficaciously resolved despite the effective parasitemia inhibition by current antimalarial agents [9]. Parasite infection and/or exaggerated immune reaction [101] contribute to malarial complications necessitating treatment emphasis on more than just pathogen clearance but extending it to host defense mechanism that do not interfere with parasitemia load.…”

“…In a bid to neutralize the disease sequelae and induce disease tolerance (anti-disease effects), albeit without reduction in parasitemia (anti-infection effects) are the adrenal glands hormones which mediate immunological-inflammatory responses but do not affect the pathogen load [9]. Other hormones play a critical role in the amelioration of malarial inflammation.…”

Crossroads between immune responses and physiological regulation: Metabolic control of resistance versus tolerance against disease

“…Cortisol‐regulated glycemic control was essential for disease tolerance in malaria, independently of parasitemia. Supplementation of glucose or glycemic control hormones other than cortisol failed to protect infected animals, highlighting the specific function of cortisol for metabolic regulation in the malaria disease state [25]. Altogether these studies show that to survive infection, the control of many metabolic variables is often as important as the capacity to control pathogen burden.…”